Systematic review of clinical practice guidelines on the management of community acquired pneumonia in children

Childhood community acquired pneumonia (CAP) is the leading cause of mortality in children under 5 years worldwide. Clinical practice guidelines (CPGs) may be limited by method of development, scope of recommendations and the quality of supporting evidence. This study systematically identified, appraised and compared the recommendations of CPGs for the management of paediatric CAP using the AGREE II tool.The systematic review yielded 1409 non-duplicate results, of which 14 CPGs were appraised. Four of the fourteen CPGs were deemed high quality. Most CPGs were considered low-medium quality with ‘rigour of development’ and ‘applicability’ the weakest domains. These areas should be considered in deriving CPGs in the future. Recommendations were generally similar across all guidelines; however, there was notable heterogeneity in three areas. This suggests the need for further evidence to guide management decisions on oxygen saturation thresholds for admission, the utility of investigations such as acute phase reactants, and the duration of antibiotic therapy.     

慢性鼻窦炎指南的评价与内容分析

背景　慢性鼻窦炎是耳鼻喉科高发疾病，对患者造成严重的影响和经济负担，但目前国内外慢性鼻窦炎诊疗指南推荐意见存在差异。目的　对慢性鼻窦炎诊疗指南进行质量评价并分析其治疗意见，为指南制定和推荐意见的采纳提供建议。方法　于2019年2月检索中英文数据库和各专业指南网站获取相关文献，同时追踪参考文献，筛选适用于青少年及成年人的推荐意见中包含对慢性鼻窦炎的治疗意见的指南。检索时间为建库至检索日期。使用临床指南研究与评估系统Ⅱ（AGREE Ⅱ）和卫生保健实践指南报告清单（RIGHT）对纳入指南的方法学质量和报告质量进行评价，并绘制气泡图和思维导图，对比分析关于慢性鼻窦炎治疗的推荐意见。结果　最终纳入8部指南，AGREE Ⅱ评价总分平均为48.76%（30.90%~73.09%），仅2部指南强烈推荐使用（得分>60%），其余6部需修订后推荐。RIGHT条目总体报告率为34.29%~65.71%，其中评审和质量控制方面报告率均为0。指南推荐一致的治疗方法包括皮质类固醇、鼻腔盐水冲洗和手术治疗，以及过敏者口服抗组胺药，可选用的措施包括细菌溶解物、黏痰溶解药、质子泵抑制剂、植物疗法、辣椒素、亮氨酸拮抗剂、鼻用呋塞米、木糖醇盐水冲洗液、次氯酸钠盐水冲洗液、含婴儿香波的盐水冲洗液，尚无统一观点的治疗措施包括抗生素、减充血剂、白三烯受体拮抗剂、IgE拮抗剂及阿司匹林加重呼吸系统疾病患者阿司匹林脱敏治疗。结论　现有慢性鼻窦炎诊疗指南制定方法及其报告质量需提高，建议纳入患者的偏好、使用统一的评价工具和考虑运用性。推荐意见有冲突时，建议参考制定方法更为严谨的指南。     

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II—Report from the German/Swiss SIOP-LGG 2004 cohort

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.     

基于网络药理学和分子对接技术的抗病毒颗粒治疗新型冠状病毒肺炎（COVID-19）的潜在物质基础研究

目的通过网络药理学及分子对接技术探寻抗病毒颗粒治疗新型冠状病毒肺炎(COVID-19)的潜在物质基础。方法借助TCMSP检索抗病毒颗粒中板蓝根、连翘、石膏、知母、芦根、地黄、广藿香、石菖蒲、郁金的化学成分和作用靶点。通过Uni Prot数据库查询靶点对应的基因,进而运用Cytoscape3.6.1构建药材-化合物-靶点(基因)网络,通过DAVID进行基因本体(GO)功能富集分析和KEGG通路富集分析,预测其作用机制,将药材-化合物-靶点网络中排名前15的成分与新型冠状病毒(SARS-Co V-2)3CL水解酶进行分子对接,同时将比枯枯灵、木犀草素、槲皮素与血管紧张素转化酶Ⅱ(ACE2)进行分子对接。结果药材-化合物-靶点(基因)网络包含药材8个、化合物75个、靶点255个。GO功能富集分析得到GO条目161个(P0.05),其中生物过程(BP)条目65个,细胞组成(CC)条目36个,分子功能(MF)条目60个。KEGG通路富集筛选得到131条信号通路(P0.05)。分子对接结果显示抗病毒颗粒中比枯枯灵、木犀草素、槲皮素等核心活性化合物与SARS-Co V-23CL水解酶的亲和力与临床推荐化学药相似。结论抗病毒颗粒中的活性化合物比枯枯灵、木犀草素、槲皮素等能通过与ACE2结合作用于PTGS2、HSP90AB1、PTGS1等靶点调节多条信号通路,从而可能发挥对COVID-19的治疗作用。     

Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia type II, is classically caused by a congenital defect in electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH). Flavin adenine dinucleotide synthase (FADS) deficiency caused by mutations in FLAD1 was recently reported as a novel riboflavin metabolism disorder resembling MADD. Here, we describe a Japanese boy with FADS deficiency due to a novel mutation (p.R249*) in FLAD1. In the asymptomatic male infant born at full term, newborn screening showed positive results with elevated C5 and C14:1 acylcarnitine levels and an increased C14:1/C2 ratio. Biochemical studies were unremarkable except for lactic acidosis (pH 7.197, lactate 61 mg/dL). A diagnosis of MADD was suspected because of mild abnormalities of the acylcarnitine profile and apparent abnormalities of urinary organic acids, although mutations in the ETFA, ETFB, ETFDH, and riboflavin transporter genes (SLC52A1, SLC52A2, and SLC52A3) were not detected. Administration of riboflavin and L-carnitine was initiated at one month of age based on the diagnosis of “biochemical MADD” despite a lack of symptoms. Nevertheless, the acylcarnitine profile was not normalized. Symptoms resembling bulbar palsy, such as vocal cord paralysis and dyspnea with stridor, were present from 3 months of age. At 4 months of age, he became bedridden because of hypoxic-ischemic encephalopathy due to fulminant respiratory failure with aspiration pneumonia. At 2 years and 5 months of age, a homozygous c.745C > T (p.R249*) mutation in the FLAD1 gene was identified, confirming the diagnosis of FADS deficiency. His severe clinical course may be caused by this nonsense mutation associated with poor responsiveness to riboflavin. Persistent lactic acidosis and neuropathy, such as bulbar palsy, may be important for diagnosing FADS deficiency. Although the biochemical findings in FADS deficiency are similar to those in MADD, their clinical symptoms and severity may not be identical.     

First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B

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A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study

ObjectiveWe aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.MethodsIn order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.ResultsWe found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.ConclusionIn this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.SignificanceEstablished and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.